The lipid mediator prostaglandin (PG) E2 has diverse actions in the kidney affecting renin release, vascular tone, and epithelial functions. The consequences of renin-angiotensin system activation by PGE2 are in direct opposition to its effects on renal vasculature and epithelia that lead to vasodilation and natriuresis. Regulation of PGE2 levels within specific renal microenvironments could provide a mechanism to control these apparently disparate actions. The long-term goal of our research is to identify genes responsible for the terminal synthesis of PGE2 in the kidney and define their capacities to regulate renal functions. To date, two microsomal PGE syntheses (mPGESI and mPGES2) have been identified that generate PGE2 from endoperoxides, and we hypothesize that mPGESI and mPGES2 have discrete functions to regulate regional synthesis of PGE2, providing a mechanism for independent control of the paradoxical actions of PGE2 in the kidney. To test this hypothesis we will use gene-targeted mice to investigate the contribution of the mPgesI and mPges2 genes to renal PGE2 generation, sodium and water excretion, and blood pressure regulation. These studies will provide new insights into prostanoid regulation of renal function and blood pressure. [unreadable] [unreadable] [unreadable]